Michel Bonin

Cross-Resistance Studies of Isogenic Drug-Resistant Breast Tumor Cell Lines Support Recent Clinical Evidence Suggesting that Sensitivity to Paclitaxel may be Strongly Compromised by Prior Doxorubicin Exposure

Less than half of breast cancer patients respond to second-line chemotherapy with paclitaxel after failing treatment with anthracyclines such as doxorubicin. A recent clinical trial by Paridaens et al. [J. Clin. Oncol. 18: 724–733, 2000] examined whether patients may derive a better clinical benefit if paclitaxel was administered before doxorubicin. While overall survival was similar regardless of the order of drug administration, a >4-fold reduction in the response rate to paclitaxel was observed after late crossover from doxorubicin, compared to the response rate to doxorubicin after late crossover from paclitaxel. This may be related to differences in the ability of the drugs to induce cross-resistance to each other. To test this hypothesis, we examined whether isogenic breast tumor cells selected for resistance to doxorubicin exhibit greater cross-resistance to paclitaxel and other drugs than identical cells selected for resistance to paclitaxel. We found that cells selected for resistance to paclitaxel showed strong resistance (≥40-fold) to paclitaxel and docetaxel, with little cross-resistance (4-fold) to doxorubicin. In contrast, cells selected for resistance to doxorubicin exhibited 50-fold resistance to doxorubicin and a dramatic 4700-fold and 14,600-fold cross-resistance to paclitaxel and docetaxel, respectively. Doxorubicin-resistant cells exhibited higher P-glycoprotein and breast cancer resistance protein (BCRP) levels than paclitaxel-resistant cells. In addition, procaspase-9 was strongly downregulated in doxorubicin-resistant cells but not in paclitaxel-resistant cells. These differences may account for the contrasting cross-resistance profiles observed for the two cell lines and may help to explain why treatment of breast cancer patients with paclitaxel appears to be compromized by prior doxorubicin exposure.

Long-term outcomes of hypofractionation versus conventional radiation therapy after breast-conserving surgery for ductal carcinoma in situ of the breast.

PURPOSE Whole-breast radiation therapy (XRT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) may decrease the risk of local recurrence, but the optimal dose regimen remains unclear. Past studies administered 50 Gy in 25 fractions (conventional); however, treatment pattern studies report that hypofractionated (HF) regimens (42.4 Gy in 16 fractions) are frequently used. We report the impact of HF (vs conventional) on the risk of local recurrence after BCS for DCIS. METHODS AND MATERIALS All women with DCIS treated with BCS and XRT in Ontario, Canada from 1994 to 2003 were identified. Treatment and outcomes were assessed through administrative databases and validated by chart review. Survival analyses were performed. To account for systematic differences between women treated with alternate regimens, we used a propensity score adjustment approach. RESULTS We identified 1609 women, of whom 971 (60%) received conventional regimens and 638 (40%) received HF. A total of 489 patients (30%) received a boost dose, of whom 143 (15%) received conventional radiation therapy and 346 (54%) received HF. The median follow-up time was 9.2 years. The median age at diagnosis was 56 years (interquartile range [IQR], 49-65 years). On univariate analyses, the 10-year actuarial local recurrence-free survival was 86% for conventional radiation therapy and 89% for HF (P=.03). On multivariable analyses, age <45 years (hazard ratio [HR] = 2.4; 95% CI: 1.6-3.4; P<.0001), high (HR=2.9; 95% CI: 1.2-7.3; P=.02) or intermediate nuclear grade (HR=2.7; 95% CI: 1.1-6.6; P=.04), and positive resection margins (HR=1.4; 95% CI: 1.0-2.1; P=.05) were associated with an increased risk of local recurrence. HF was not significantly associated with an increased risk of local recurrence compared with conventional radiation therapy on multivariate analysis (HR=0.8; 95% CI: 0.5-1.2; P=.34). CONCLUSIONS The risk of local recurrence among individuals treated with HF regimens after BCS for DCIS was similar to that among individuals treated with conventional radiation therapy.

Impact of Boost Radiation in the Treatment of Ductal Carcinoma In Situ: A Population-Based Analysis

PURPOSE To report the outcomes of a population of women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and radiation and to evaluate the independent effect of boost radiation on the development of local recurrence. METHODS AND MATERIALS All women diagnosed with DCIS and treated with breast-conserving surgery and radiation therapy in Ontario from 1994 to 2003 were identified. Treatments and outcomes were identified through administrative databases and validated by chart review. The impact of boost radiation on the development of local recurrence was determined using survival analyses. RESULTS We identified 1895 cases of DCIS that were treated by breast-conserving surgery and radiation therapy; 561 patients received boost radiation. The cumulative 10-year rate of local recurrence was 13% for women who received boost radiation and 12% for those who did not (P=.3). The 10-year local recurrence-free survival (LRFS) rate among women who did and who did not receive boost radiation was 88% and 87%, respectively (P=.27), 94% and 93% for invasive LRFS (P=.58), and was 95% and 93% for DCIS LRFS (P=.31). On multivariable analyses, boost radiation was not associated with a lower risk of local recurrence (hazard ratio = 0.82, 95% confidence interval 0.59-1.15) (P=.25). CONCLUSIONS Among a population of women treated with breast-conserving surgery and radiation for DCIS, additional (boost) radiation was not associated with a lower risk of local or invasive recurrence.

Multigene Expression Assay and Benefit of Radiotherapy After Breast Conservation in Ductal Carcinoma in Situ.

Background Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994-2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score-adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.Abstract Background: Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods: Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994–2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score–adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results: The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions: The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

Abstract S5-04: A large prospectively-designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation

Background: DCIS patients need better tools to align the aggressiveness of treatment with the aggressiveness of their disease. The DCIS Score (DS) was validated as a predictor of ipsilateral breast recurrence (IBR; DCIS or invasive) in 327 E5194 patients treated by breast-conserving surgery (BCS) without radiation (RT) (Solin,2013). This Ontario population based DCIS study of 3335 women with DCIS from 1994 to 2003 (Rakovitch,2013) was conducted to test the DCIS Score as a predictor of recurrence risk in patients treated with BCS alone and in patients treated with BCS+RT. Methods: REMARK guidelines were followed. Breast pathologists centrally reviewed all HE 718 received BCS without RT (N=571 with CM) and 846 received BCS+RT (N=689 with CM). Median follow-up was 9.4 years. Among 1260 pts with CM, 100 pts treated with BCS alone had an IBR (DCIS, N=44; invasive, N=57); 86 pts treated with BCS+RT had an IBR (DCIS, N=32; invasive, N=55). In the primary analysis, among 571 patients treated by BCS alone with CM the continuous DS was significantly associated with IBR in ER+ patients (HR 2.26; 95%CI 1.41,3.59; P=0.001) and in all patients (HR 2.15; 95%CI 1.43,3.22; P= Conclusions: DCIS Score quantifies recurrence risk for DCIS patients treated by BCS with or without RT. Integrating the DCIS Score with established risk factors, such as multifocality, age, and tumor size, can help identify DCIS patients treated with BCS alone with low 10 year risk ( Citation Format: Eileen Rakovitch, Sharon Nofech-Mozes, Wedad Hanna, Frederick L Baehner, Refik Saskin, Steven M Butler, Alan Tuck, Sandip Sengupta, Leela Elavathil, Prashant A Jani, Michel Bonin, Martin C Chang, Elzbieta Slodkowska, Joseph M Anderson, Farid Jamshidian, Diana B Cherbavaz, Steven Shak, Lawerence Paszat. A large prospectively-designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S5-04.